ES2314508T3 - METHOD OF PREPARING ORGANOMAGNETIC COMPOUNDS. - Google Patents

Abstract

The present invention is directed to a reagent for use in the preparation of organomagnesium compounds as well as to a method of preparing such organomagnesium compounds. The present invention furthermore provides a method of preparing functionalized or unfunctionalized organic compounds as well as the use of the reagents of the present invention in the preparation of organometallic compounds and their reaction with electrophiles. Finally, the present invention is directed to the use of lithium salts - LiY in the preparation of organometallic compounds and their reactions with electrophiles and to an organometallic compound which is obtainable by the disclosed method.

Description

Method of preparing compounds of Organomagnesics

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The present invention relates to a reagent for use in the preparation of organomagnesic compounds as well as to a procedure for preparing such compounds Organomagnesics The present invention further provides a procedure to prepare organic compounds. Also provides the use of the reagents of the present invention in the preparation of organometallic compounds and their reaction with electrophiles. Finally, the present invention is directed to the use of salts of lithium - LiY in the preparation of organometallic compounds and their reactions with electrophiles and organometallic compounds that obtained by the described method.

Background of the invention

Polyfunctional Organometallic Compounds they are important intermediaries in organic synthesis modern. ^ {[1]}

One of the best preparative methods of these reagents is the exchange reaction halogen metal. While the exchange Br / Li is a rapid reaction that occurs at low temperature, the corresponding Br / Mg exchange is considerably slower, which is an important synthetic limitation by different reasons:

(i)

he exchange requires a higher reaction temperature and so both is not compatible with many functional groups,

(ii)

he slow exchange Br / Mg especially in rich aromatic bromides in electrons competes with the removal of HBr from the bromide of alkyl that also occurs during the reaction (usually isopropyl bromide) and therefore results in low yields A catalysis of the Br / Mg exchange reaction It would be a highly desirable process.

Recently, the inventors have demonstrated that highly functionalized aryl- and heteroaryl magnesium halides can be prepared quickly using an iodine-magnesium exchange reaction. [2] As the exchange reagent, i -PrMgX (X = Cl, Br ) has proven to be the most convenient. In some cases, this exchange reaction could extend to some aryl and heteroaryl bromides when a potent electron-attractant and (or) a chelating group was present to coordinate i -PrMgX and perform the "intramolcular" Mg exchange. 3]}

Basically, the I / Mg exchange reaction is an excellent method for preparing aryl and heteroaryl functionalized compounds. Its main disadvantage is the need to use organic iodides sometimes unstable, and often expensive or not commercially available. The alternative of using aryl bromides as substrates for the Br / Mg exchange is known, but was strongly limited only to highly reactive aryl bromides (with several electron-attractant groups) due to the low exchange reaction rate using i -PrMgCl or i -Pr2 Mg.

Therefore, it is an underlying problem of the present invention provide an improved method for Prepare organomagnesic compounds. It is another underlying problem of the present invention provide an organomagnetic compound, that has a greater reactivity with an electrophile (E +).

These problems are solved by the subject-matter of independent claims. Preferred embodiments are set forth below in the dependent claims.

Summary of the Invention

The inventors found that using the mixture organometallic R1 (MgX) n \ cdotLiY, occurs a rapid exchange reaction leading to the reagents of Desired Grignard in high yields under mild conditions and allowing the preparation of many Grignard compounds functionalized that were previously only available through of Br / Mg exchange reactions with mediocre yields. He procedure of the present invention considerably facilitates the preparation of aryl-, heteroaryl-, alkenyl- compounds, alkynyl-, or alkyl-magnesium and finds wide applications in university laboratories as well as industry for a use to big scale. Basically, the process of the present invention corresponds to the following reaction scheme:

one

According to a first aspect, the invention is directed to a reagent to be used in the preparation of organomagnesic compounds, the reagent having the formula general

R 1 (mgx) n LiY

in where,

n is 1 or 2;

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R1 is a heteroaryl C 4 -C 24 substituted or unsubstituted, which It contains one or more heteroatoms such as B, O, N, S, Se, P, F, Cl, Br, I, Yes; a C 1 -C 20 alkyl, an alkenyl C 2 -C 20 or an alkynyl C 2 -C 20 linear or branched, substituted or not substituted; or a C 3 -C 20 cycloalkyl substituted or unsubstituted;

X and Y are independently or together Cl, Br or I, preferably Cl; HalO_ {n} (where n = 3, 4); a carboxylate of formula RCO2; an alkoxide or phenoxide of formula RO; a dialkoxide of the formula LiO-R-O; a disilazide of formula (R 3 Si) 2 N; a thiolate of SR formula; RP (O) O2; or SCOR; where R is defined as R1 above; C1 {C} {C} {linear} or branched, substituted or unsubstituted or C 3 -C 20 cycloalkylamine of formula RNH; dialkyl / arylamine of formula R 2 N (where R is defined as more above or R2 N represents a heterocyclic alkylamine); phosphine of formula PR2 (where R is defined as above or PR2 represents a heterocyclic phosphine); O_ {n} SR (where n = 2 or 3); or X = R1 as defined above.

It is noted that X and R1 will normally be the same substituent in the case of X = R1, however also it may be different in the scope of the definition indicated for R1.

It is explicitly stated that this invention also encompasses compounds of formula XMg-R1 -MgX \ cdotLiY (en say, where n = 2). In addition, whenever indicated "R2_" in this application, (for example in R2_N or PR_ {2}), both R can be the same or different according to the definition indicated above.

Additionally, it is noted that the exchange rate using R 1 (MgX) n • CYY can be increased further if
X = R_ {1}. This reagent is achieved by the addition of polyethers or polyamines that lead to the formation of a new reagent (R 1) 2 Mg • LYY.

Thus, in a preferred aspect, the reagent is (R 1) 2 Mg • LYY.

The mechanism involved in this finding Unexpected can be explained as follows:

2

It is noted that this system normally requires use at least one solvent as summarized below and at least one additive (see also below). For example, THF can be used as solvent alone or in combination with other solvents, and a ether-crown as indicated above, could be used as an additive, which is directly involved in the formation of the reagent which is (R 1) 2 Mg • LYY.

There could be exceptions to this general rule in which some solvents may also be used as additives or vice versa. For example, it is possible to prepare (R 1) 2 Mg • in pure dioxane as summarized below.

Dioxane has several advantageous properties, it is a solvent for example, cheap, non-toxic, industrial, not easily flammable, with high boiling point, not very hydroscopic, which is easy to handle and dry - therefore, practically an ideal solvent and additive. And, it serves as Suitable solvent and additive in the reactions above.

As an example for the reaction above, the reagent is prepared in situ simply by treating a solution of i-PrMgCl • with a crown ether such as 15-crown-5 (which gives the best result; see entry 4 of Table 3) or in general with another polyether or polyamine, see Table 3.

Surprisingly, and as mentioned more Above, the cheapest way to achieve speed increase it is to use the addition of dioxane (10% vol) which leads to a 100% conversion (4-bromoanisole to 4-methoxy-phenylmagnesium) after 24h of reaction time. Comparing, performing the same reaction with i-PrMgCl \ cdotLiCl in THF gives only one 31-39% conversion after the same time of reaction. It is also important to note that the addition of 15-crown-5 or dioxane a i-PrMgCl without LiCl does not lead to any increase in speed.

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Thus, the addition of 1,4-dioxane (or related polyethers such as oligo- or polyethylene glycol ethers or polyamines) will further increase the exchange reaction such as Br / Mg exchange and allows for example to convert bromides into the corresponding Grignard reagent under conditions that before They resulted in an incomplete reaction. Other explanations for This can be found in the "Examples" chapter.

According to a preferred embodiment, the reagent consists of R1 (MgX) n and LiY in a molar ratio between 0.05-6.0.

According to a preferred aspect, Y is Cl in R1 (MgX) n -LiY or LiY. In other even more preferred aspect, R1 (MgX) D -LiY is i-PrMgCl \ cdotLiCl or sec-BuMgCl \ cdotLiCl. Molar relations preferred among i-PrMgCl or sec-BuMgCl and LiCl are from 0.05 to 6.0.

According to another preferred aspect, and in R 1 (MgX) n • LiY or LiY is tert-butylate or sec-butylate. Other lithium salts such as lithium perchlorate, lithium acetylacetonate, lithium bromide, lithium iodide and lithium tetrafluoroborate se also included within this invention, however, are aspects less preferred

According to a second aspect, the present invention provides a method for preparing compounds Organomagnesics, which consists of the following steps:

a) provide a compound of formula general

R2 A

in where

quad

R 2 is defined as R 1 or is a metallocene substituted or unsubstituted such as ferrocene.

quad

A is H, Cl, Br, I, preferably Br, or a group of general formula:

S (O) n -R 3

quad

where

quad

n = 0, 1 or 2

quad

or a group of general formula:

P (O) R 3 {2}

quad

where R 3 is independently defined as R1 above. It is emphasized that R3 in this context can Be the same or different.

quad

or P (O) R 3 2 represents a heterocyclic phosphinoxide;

b) provide a reagent in accordance with the formula R1 (MgX) n \ cdotLiY as defined higher;

c) make the reaction of the compounds provided in steps a) and b) under the appropriate conditions; obtaining in this way the respective organomagnesic compound.

The organomagnesic compound obtained in c) It can additionally be isolated. It is observed that, if R2 is a aryl or heteroaryl compound, this may be substituted by one or more FG groups, where FG is preferably selected from F, Cl, Br, CN, CO 2 R, OR, OH, NR 2, NHR, NH 2, PR 2, P (O) R2, CONR2, CONHR, SR, SH, CF3, NO 2, C = NR, R (where R is defined as R 1 above). Preferred examples of R2 A are bromonaphthalene, Bromophenanthrene, Bromoanisole, Bromothiophene, Bromothiazole, bromopyridine, 1-Bromo-3-fluorobenzene, 3-bromobenzothiophene, 1,2-dibromobenzene, 1,2,4-tribromobenzene and derivatives thereof as well like the other compounds that are revealed later.

Mainly it is possible to use all kinds of FG functional group that are cited, for example in the following references, but not limited to them:

a) Handbook of Grignard reagents ; edited by Gary S. Silverman and Philip E. Rakita ( Chemical industries ; v. 64).

b) Grignard reagents New Developments ; edited by Herman G. Richey, Jr., 2000 , John Wiley & Sons Ltd.

c) Methoden der Organischen Chemie , Houben-Weyl , Band XIII / 2a, Metallorganische Verbindungen Be, Mg, Ca, Sr, Ba, Zn, Cd. 1973 .

d) The chemistry of the metal-carbon bond , vol 4. edited by Frank R. Hartley. 1987 , John Wiley & Sons .

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According to another embodiment, the reagent of general formula R 1 (Mg) n • lYY provides by reaction of R 1 X, Mg and LiY or by reaction of R1 (MgX) n and LiY, or by reaction of R1 Li and MgXY. It is noted that some components that are used in this reaction they are commercially available in Aldrich or Strem CAS [1068-55-9])

According to one embodiment, the reagent provided in step b) is used in a molar amount of 0.4-6.0 moles per mole of compound provided in step a). In general, the reagent of the present invention with the general formula R1 (MgX) n \ cdotLiY can add up to 6.0 moles of the reagent per 1 mole of the compound provided in a) (general formula R2 A). A limit lower than 0.4 mol per mole of R2 A means that the effects of present invention, that is, the dramatic increase in conversion reaction speed:

3

they may not be reached, if use values below this limit.

It is observed that in the formula above, n it may be different in R1 (MgX) n \ cL and Y R 2 (MgX) n • LiY.

The reaction above is carried out in an appropriate solvent. Preferably, the solvent, in which
R 1 (MgX) n is dissolved, it is an inert aprotic solvent, for example tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, dibutyl ether, tert-butyl methyl ether, dimethoxyethane, dioxane, triethylamine, pyridine, ethyldiisopropylamine, dichloromethane, 1,2-dichloroethane, dimethylsulfide, dibutyl sulfide, benzene, toluene, xylene, pentane, hexane or heptane, or combinations thereof and / or the solvents normally used to carry out the Grignard reaction that They are indicated in the literature cited above.

As summarized above, add one or more solvent additives may result in a reagent (R 1) 2 Mg • improved. This additive can be selected from polyethers and polyamines, in particular ethers corona, dioxanes, oligo- or poly-ethylene glycol ethers, derivatives of urea, amides of formula RCONR2 (where R is defined as in the claim 1, and the radicals may be the same or different), more preferably 1,4-dioxane or 15-crown-5 or combinations of same. Other examples of additives that can be used in the The present invention is listed in Table 3, below.

According to another embodiment, the dissolution above R 1 (MgX) n • LYY is 0.05 to 3.0 M, preferably 1.0-2.5 M. As a general rule, higher concentration of the solution, the better the reaction will work global. However, generally, solutions of R 1 (MgX) n • of more than 3 M will not be soluble and therefore will not play their part in this invention.

The use of R 1 (MgX) n • as a powder (without solvents or coordinated solvents) is also possible and Convenient for storage.

According to another aspect, the invention provides a procedure to prepare organic compounds functionalized or non-functionalized, comprising the steps a) -c) as defined above, and d) do the reaction of the organomagnesic compound obtained with an electrophile E + or E organic or inorganic.

The reaction follows the reaction scheme:

4

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Examples of electrophiles that are used commonly for reaction with Grignard reagents are cited in references a) - d) mentioned above, but are not limited to they.

Specific examples of electrophile are RCHO, RCOX, X_ {n} PR_ {3-n} (n = 1, 2, 3), X_ {P} O (R) {3-n} (n = 1, 2, 3), RX, RCO2R, RCN, R_ {n} Si-X_ {4-n} (n = 0, 1, 2, 3), R_ {n} SnX_ {4-n} (n = 0, 1, 2, 3) or RSSO_R (n = 0, 1, 2), RNO2, RNO, RN = NSO2R, RC = NR, B (OR) 3,

where

X is a halogen or a group S (O) n R, where n = 0, 1 or 2, and R is defined generally as R1 above.

Again, it is noted that where two or three Rs are found in a formula, these may be the same or different one of the other.

However, the invention is not restricted to these examples and improved reactions of the reagents are observed of Grignard complexed with LiY with several electrophiles for all The types of electrophiles.

The procedures mentioned above are carried out in a temperature range between -78º and 80ºC, preferably at room temperature. The upper limit of the range of temperature is usually the boiling temperature of the respective solvent used.

According to another aspect, the invention is directs the use of the reagent R 1 (MgX) n • in the preparation of Organomagnesic compounds and their reactions with electrophiles.

The invention further describes the use of LiY in the preparation of organometallic compounds and their reactions with electrophiles, where Y is defined as above. It is observed that in particular, LiCl dramatically increases the speeds of conversion of exchange procedures above. For compare, see attached table Table 2.

According to a final aspect, the invention provides an organomagnesic compound that is obtainable by the procedure according to the second aspect that is defined more above. It is observed that the complexed product of this reaction is say, a product of general formula R2 (MgX) n \ cdotLiY, has much higher reactivity with electrophiles (E +) or (E) than the reagents that are previously used and also their solubility in solvents Appropriate respective (see above) is higher.

Thus, through the procedures herein invention it is possible to reach conversion rates of up to 100% compared to only mediocre yields of the methods previously used in the field.

The present invention will be described later. referring to the following figures and examples; without However, it is understood that the present invention is not limited to such Figures and examples.

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Summary description of the figures

Fig. 1 shows the conversion of 4-Bromobenzonitrile at -7 ° C to bromide 4-cyanophenylmagnesium.

Fig. 2 shows the conversion of 4-Bromoanisole at room temperature to bromide of 4-methoxyphenylmagnesium.

Fig. 3 Grignard reagents prepared on the 90% Br / Mg exchange using i-PrMgCl • ClCl (reaction conditions are given below each formula).

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Detailed description of the invention

The present invention will be described more completely later with reference to the figures that accompany. The following embodiments are provided so that this revelation be rigorous and complete, and communicate completely the scope of the invention to those who are experienced in the matter.

Unless defined otherwise, all technical and scientific terms used here have the same meaning that he who commonly understands someone experienced in the area to which this invention belongs. All the publications and other references mentioned here are incorporated by complete reference

As used herein, the terms "alkyl", "alkenyl" and "alkynyl" refer to compounds C_ {1} -C_ {20} substituted and unsubstituted, linear and branched. Preferred ranges for these compounds they are C 1 -C 10, preferably C 1 -C 5 (lower alkyls) and C 2 -C 10, preferably C 2 -C 5, respectively, for alkenyls and alkynyls. The term "cycloalkyl" generally refers to C_ {3} -C_ {20} substituted and unsubstituted, linear and branched. Here, the preferred ranges are C 3 -C 15, more preferably C_ {3} -C_ {8}.

The term "aryl" as used herein is refers to C4-C24 aryl substituted or not substituted, by "heteroaryl", is meant a heteroaryl C 3 -C 24 substituted or unsubstituted, which contain one or more heteroatoms such as B, O, N, S, Se, P. Ranges Preferred for both are C 4 -C 15, plus preferably C 4 -C 10.

The inventors now find that it is possible to catalyze exchange reactions, for example the Br / Mg exchange reaction using the R 1 (MgX) n -LiY complex, for example i-PrMgCl • ClCl. As an example, 1-bromo-3-fluorobenzene (1a) undergoes a slow incomplete exchange reaction with i-Pr2 Mg (1.1 equivalents, room temperature, 3h) giving after reaction with benzaldehyde the corresponding alcohol 2a isolated in 50% yield. [3a] On the other hand, the reaction with i- PrMgCl • under the same conditions provides magnesium reagent 3a with a 95% yield contrasted by gas chromatography analysis using Tetradecane as internal standard. After a reaction with benzaldehyde, alcohol 2a is obtained isolated in a yield of 85% (Scheme 1).

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Scheme one

5

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Various aryl fluoro- and bromides Chloro-substituted easily become the corresponding magnesium reagents at room temperature using i-PrMgCl \ cdotLiCl. The conversion is completed without 0.5-0.3 h, which is in sharp contrast to the previous procedures that involved the use of i-PrMgCl or i-Pr2Mg (Scheme 2).

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Scheme 2

6

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Reaction times for the preparation of arylmagnesium reagents with i-PrMgCl \ cdotLiCl.

Similarly, this catalysis can be applied to heterocyclic systems such as 2,6-dibromopyridine (1b). This dibromide also requires the use of i-Pr2 Mg [3a] or i-PrMgCl [3f] to carry out the Br / Mg exchange reaction. Under these conditions, the reaction with benzaldehyde provides the desired 2ba alcohol in only 42% yield. [3f] We have again observed the superiority of i -PrMgCl • as an exchange reagent and have observed a conversion of 92 % after a reaction time of 1 h at 25 ° C while the use of i-Pr2 Mg requires a reaction time of 4 h. Using the new reagent i -PrMgCl • ClCl, the desired reaction product (2ba) is obtained isolated in a yield of 89% (Scheme 1). Good results were also obtained in the reactions of Grignard reagents formed (3b) from 2,6-dibromopyridine (1b) with other electrophiles (Table 1, entries 1-3). The Br / Mg exchange in the case of 3,5-dibromopyridine can be carried out in 15 min at -10 ° C and the reaction with allyl bromides provides 2ca allylated pyridine with excellent yield (Table 1, entry 4). A 3-bromopyridine can also be easily converted into the corresponding Grignard reagent, 3v, in 5 min. at room temperature and led after the reaction with allyl bromide to 3-allylpyridine, 2va, with an almost quantitative yield. Other heterocyclic systems such as 2-bromothiophene, 3-bromothiophene, 3-bromobenzothiophene and 2-bromothiazole react easily with i- PrMgCl? At room temperature and after reaction with different electrophiles provide the corresponding 2ra-2ua products with yields of good at Excellent (Table 1, entries 29-32). It should be noted that our approach opens the way for the synthesis of different aldehydes through the reaction of Grignard 3r reagents with different electrophiles, because the thiazole group can easily convert to the aldehyde function.

This behavior is general, and the use of i- PrMgCl? Allows faster Br / Mg exchange compared to i-PrMgCl or i-Pr2 Mg. Also, it dramatically increases the conversion by giving the desired organomagnesic reagent without the need for an excess of reagent (usually 1.1 or 1.05 equivalents of i.PrMgCl • ClCl) is used. In addition, the reactivity of the resulting magnesium reagent also seems to improve and leads to higher yields in entrapment reactions with electrophiles. Grignard reagents sterically hindered with substituents in the ortho position as 31 are obtained in 12 h of reaction at room temperature providing, after the addition of benzaldehyde, the desired alcohol 21a in a 90% yield (Table 1, entry 21). The richer in electrons the aromatic ring is, the slower the exchange reaction using i-PrMgCl. However, 2-methoxy-1-bromobenzene (1h) is converted into the desired 3h magnesium reagent in more than 90% yield after a reaction time of 24 h at room temperature. After its reaction with PhSSPh, the thioeter 2ha is obtained in a 90% yield (entry 12). A range of different electrophiles react with these Grignard reagents after a transmetalation step with CuCN • 2Cl [4] allowing alilations and acylations (entry 14).

Chlorine and methoxy aryl bromides highly substituted can be easily converted into reagents of Grignard 3i, j. After the reaction with ClPPh2 and the one in conditions oxidizers, phosphine oxides 2ia, are obtained in good yields (entries 15, 16). These types of compounds are from interest in relation to the P-ligands for the asymmetric catalysis. ^ [5]} Also functions as a group cyano, they are tolerated. So, the reaction of 4-Bromobenzonitrile in THF at -7 ° C leads to reagent of desired arylmagnesium (3d) in only 50% conversion using i-PrMgCk while with i-PrMgCl · ClCl is observed over 90% (Scheme 3). The addition of benzaldehyde provides the 2nd alcohol in 81% yield, while reagent allylation of arylmagnesium (3d) with allyl bromide leads to Corresponding 4-allylbenzonitrile in a 92% yield (entries 5, 6 of Table 1). See Fig. 3 for Additional Information.

Grignard 3e, f reagents are obtained in 3 h at 0 ° C and showed a good yield after the reactions with several electrophiles (entries 5-10). Usually non-reactive compounds such as bromonaphthalene derivatives and Bromophenanthrene are easily converted into the reagents of Grignard corresponding 3m, n (entries 22-25) that easily both react with benzaldehyde (entries 22, 24) and with alil bromide with good yields (entry 23). After one catalytic transmetalation with CuCN • 2Cl (0.2 equivalents) and a reaction with ethyl-4-iodobutyrate for 4 h at -10 ° C, 81nb cross coupling product is obtained in 81% performance (entry 25). As indicated above, several dichloro-substituted Grignard reagents as 3rd and 3p can be easily prepared and react with aldehydes aliphatic and aromatic, obtaining the alcohols corresponding 2oa, 2pa in 83 and 92% performance (tickets 26, 27). Also the ester function can be tolerated in the position ortho, in this way, the 3q magnesium reagent was prepared in 12 h at -45 ° C and the reaction with allyl bromide led to the formation of corresponding allyl ester 2qa in 82% yield.

Surprisingly, in the case of 1,2-dibromobenzenes only occurs a reaction of a simple exchange providing the desired Grignard reagent (3k) (-15 ° C, 1.5 h) in an almost quantitative yield, such as indicates the analysis by gas chromatography of aliquots of the reaction. The chloride reaction of 2-bromophenylmagnesium (3k) with 3-iodo-2-cyclohexen-1-one It produces the expected dwarf (2kc) in 86% yield. He Grignard 3k reagent also showed good activity against different electrophiles (entries 17-20). In the entries 21-33 of Table 1 are shown differently variations of these reactions and several new reagents of important magnesium

Since the stereoselective preparation of Stereochemically well defined alkylmagnesium compounds E- or Z- is not possible by direct magnesium insertion into well-defined alkenyl halides E or Z, the reaction of iodine-magnesium exchange could be the only way of preparing stereochemically pure alkenylmagnesium derivatives E i Z. ^ [6]} Recently, we have shown that the reactions of iodine-magnesium exchange in the case of iodides of alkenyl require the presence of attractive electron groups in the α or β positions to facilitate the reaction of exchange. ^ {7] This led us to investigate the preparation stereoselective alkenylmagnesium reagents by I / Mg exchange of non-activated iodine alkenes. So, the reaction exchange of (E) -1-bromohexane occurs by providing chloride (E) -1-hexenylmagnesium (4a) (-25 ° C, 10 h) in almost quantitative yields (analysis by chromatography of aliquots of the reaction). The reagent reaction of Grignard 4a with t-BuCHO led to the formation of corresponding alcohol 5a with excellent performance. This surprisingly low temperature will allow the presence of numerous functional groups. Also, we observe a reaction of fast exchange with good conversion (GC) in the case of a chiral cyclic alkenyl iodide. The subsequent reaction of 4b magnesium reagent with allyl bromide proceeds with a good performance, which opens access to different allylic alcohols α-substituted chiral (Scheme 3).

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Scheme 3

7

It is also possible to do the Br / Mg exchange in vinyl systems. Thus, 1,2-dibromocyclopentene easily reacts with i-PrMgCl \ cdotLiCl to room temperature to produce the stable Grignard reagent 4c that after the reaction with cyclohexylaldehyde gave alcohol 5b in Good performance

Scheme 4

8

Reagent 4c is completely stable at room temperature for weeks, but the addition of quantities catalytic Cu (I) and Cu (II) led to the formation of cyclopentine which, in the presence of an additional equivalent of magnesium or lithium compounds, reacts with the formation of new Grignard 4d species, e. The addition of benzaldehyde gave the Corresponding alcohols in good yields.

Scheme 5

9

Other lithium salts such as perchlorate lithium, lithium acetylacetonate, lithium bromide, iodide lithium and lithium tetrafluoroborate were also tested, but they gave a less efficient catalysis (Fig. 2).

Although the mechanism of catalysis is not elucidated, the inventors assume that the role of lithium chloride is to activate the i-PrMgCl by increasing the nucleophilic character of the isopropyl group by formation of a type 6 magnesium species, leading to the intermediate -ato of type 7 and finally to the organomagnetic species PhMgCl \ cdotLiCl (8).

Scheme 6

10

The formation of complexes of the species of arylmagnesium with LiCl as indicated for 8 (scheme 6) can also be responsible for the increase in reactivity of these magnesium organometallic. [4]

As an example, the inventors found a simple procedure for catalysis of the reaction of Br / Mg exchange of aryl and heteroaryl bromides with the complex i-PrMgCl \ cdotLiCl. This allows you to prepare a range of new polyfunctional organomagnetic compounds based on cheap aryl and heteroaryl bromides containing the majority of the important functionalities for organic synthesis.

Examples

Preparation of the reagent i-PrMgCl • Cl : Magnesium chips (110 mmol) are placed in an Ar stream flask containing anhydrous LiCl (100 mmol) and 50 ml of THF are added. The solution of i-PrCl (100 mmol) in 50 ml of THF is added slowly and the mixture is stirred at room temperature and the Grignard reaction begins in a few minutes. The reaction mixture is stirred after the exothermic reaction is completed for an additional 12 h at room temperature. The slightly dark solution of i-PrMgCl • ClCl is transferred to a new flask under an Ar atmosphere and thereby removes excess Mg.

Typical procedure Preparation of Phenyl- (4-cyanophenyl) methanol 2nd:

In a dry 10 ml flask with a flow of Argon, equipped with a magnetic stirrer and a septum, was put 4-bromobenzonitrile (182 mg, 1mmol). THF was added dry (1 ml), the reaction mixture was cooled to -7 ° C and i-PrMgCl-LiCl (1 ml, 1.1 M in THF, 1.1 mmol) was then added dropwise. The exchange Br / Mg was completed after 3 h (checked by chromatography analysis of gases from reaction aliquots, conversion greater than 90%) and Benzaldehyde (116.6 mg, 1.1 mmol) was added. Reaction mixture it was stirred for 0.5 h at 7 ° C and then interrupted with a saturated NH4Cl solution (2 ml).

The aqueous phase was extracted with ether (3x4 ml) and the organic fractions were lifted with brine (5 ml), dried (Na2SO4) and concentrated in vacuo . The crude residue was purified by flash chromatography (dichloromethane) resulting in benzyl alcohol (2nd) as a colorless oil (169.5 mg, 81%). H 1 -RMN (CDCl 3, 200 MHz): δ = 7.91-7.85 (m, 2 H); 7.65-7.46 (m, 3 H); 7.38-7.30 (m, 4 H); 5.86 (s, IH); 2.42 (s, 1 H, OH).

Preparation of 3-allyl-5-bromopyridine, 2nd:

A 10 ml dry and argon stream flask, equipped with a magnetic stirrer and a septum, was charged with i-PrMgCl • ClCl (1 ml, 1.05 M in THF, 1.05 mmol), the reaction mixture it was cooled to -15 ° C and 3,5-dibromopyridine was added in one portion (236.9 mg, 1 mmol). The temperature increased to -10 ° C and the Br / Mg exchange was completed after 15 minutes (checked by analysis by aliquot gas chromatography of the reaction, conversion of more than 98%), allyl bromide (140.6 mg) was added , 1 mmol). The reaction mixture was stirred for 1 hour at -10 ° C and then, quenched with a saturated solution of NH 4 Cl (2 ml). The aqueous phase was extracted with ether (3 x 4 ml), dried (Na2SO4) and concentrated in vacuo . The crude residue was purified by flash chromatography (dichloromethane) resulting in 3-allyl-5-bromopyridine (2ca) as a colorless oil (184.2 mg, 93%). 1 H-NMR (CDCl 3, 200 MHz): δ = 8.48 (d, J = 2.2 Hz, 1 H); 8.32 (d, J = 1.6 Hz, 1 H); 7.61 (dd, J = 2.2 Hz, J = 1.6 Hz, 1 H); 5.89-5.68 (m, 1 H); 5.08-5.01 (m, 1 H); 3.32 (brd, J = 6.8 Hz, 1 H).

Preparation of (2-Bromophenyl) (phenyl) methanone 2ka:

A dry 10 ml flask with a stream of argon, equipped with a magnetic stirrer and a septum, was loaded with i-PrMgCl • ClCl (1 ml, 1.05 M in THF, 1.05 mmol), the mixture of The reaction was cooled to -15 ° C and 1,2-dibromobenzene (235.9 mg, 1 mmol) was then added dropwise. The Br / Mg exchange was completed after 1.5 hours (checked by analysis by aliquot gas chromatography of the reaction, conversion greater than 98%) and a solution of CuCN • 2LiCl (0.1 ml, 1.0) was added M in THF, 0.1 mmol). After stirring for 10 minutes at -15 ° C, benzoyl chloride (140.6 mg, 1mmol) was added. The reaction mixture was stirred for 1h at -15 ° C and then quenched with a saturated solution of NH4Cl (2ml) and also 5 drops of concentrated NH3 were added. The aqueous phase was extracted with ether (3 x 4 ml) and the organic fractions were washed with brine (5 ml), dried (Na2SO4) and concentrated in vacuo . The crude residue was purified by flash chromatography (dichloromethane) resulting in the ketone ( 2ka ) as white crystals (219.3 mg, 84%). 1 H-NMR (CDCl 3, 200 MHz): δ = 7.86-7.78 (m, 2 H); 7.68-7.56 (m, 2 H); 7.52-7.30 (m, 5 H).

TABLE 1 Type 2 products obtained by reacting organomagnesic reagents 3 obtained by exchanging aryl and heteroaryl bromides with i -PrMgCl? With several electrophiles

eleven

TABLE 1 (continued)

12

TABLE 1 (continued)

13

TABLE 1 (continued)

14

TABLE 1 (continued)

fifteen

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TABLE 2

16

Example of improved reagent behavior (R 1) 2 Mg • LY

The reaction of aryl bromide 1 with i-PrMgCl-LiCl leads only to the mixing, while with i-PrMgCl • ClCl in THF with the addition of 15-crown-5 it reaches a 91% conversion to the corresponding Grignard reagent 2.

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17

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TABLE 3 Effect of the addition of additives in the formation of 4-methoxyphenylmagnesium chloride at 25 ° C after 24 hours of reaction time (1 M solution in THF)

18

19

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Abbreviations

15-C-5:

15-crown-5

PEG 250:

Polyethylene Glycol, average molecular weight 250 g / mol

DMPU:

tetrahydro-1,3-dimethyl-2 (1 H ) -pyrimidinone,

MTBE:

2-methoxy-2-methyl propane,

TMU:

N, N, N ', N' -tetramethyl-urea,

NMM:

N- methylmorpholine

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Procedure A :

Was added 4-Bromoanisole to the pre-agitated mixture of secBuMgCl • and Additive at 25 ° C

Procedure B :

the additive was added to the mixture preagited from secBuMgCl \ cdotLiCl and 4-Bromoanisole

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References

[1] A. Boudier , LO Bromm , M. Lotz , P. Knochel , Angew. Chem ., 2000 , 112, 4584; Angew Chem. Int . Ed. 2000 , 39, 4414.

[2] a) P. Knochel , W. Dohle , N. Gommermann , FF Kneisel , F. Kopp , T. Kom , I. Sapountzis , VA Vu , Angew. Chem 2003 , 115, 4438, Angew. Chem. Int . Ed. 2003 , 42, 4302; b) L. Boymond , M. Rottländer , G. Cahiez , P. Knochel , Angew. Chem 1998 , 110, 1801; Angew Chem. Int . Ed. 1998 , 37, 1701;

[3] a) M. Abarbri , F. Dehmel , P. Knochel , Tetrahedron Lett . 1999 , 40, 7449; for the synthesis of arylmagnesium species starting from aryl bromides using lithium organomagnesiates to carry out the Br / Mg exchange reaction: b) K. Kitagawa , A Inoue , H. Shinokubo , K. Oshima , Angew. Chem 2000 112, 2594; Angew Chem. Int . Ed. 2000 39, 2481; c) To Inoue , K. Kitagawa , H. Shinokubo , K. Oshima , J. Org. Chem 2001 , 66, 4333; d) A. Inoue , K. Kitagawa , H. Shinokubo , K. Oshima , Tetrahedron 2000 , 56, 9601; e) F. Trécourt , G. Breton , V. Bonnet , F. Mongin , F. Marsais,; G. Queguiner , Tetrahedron Lett . 1999 , 40, 4339. f) F. Trécourt , G. Breton , V. Bonnet , F. Mongin , F. Marsais,; G. Quéguiner , Tetrahedron 2000 , 56, 1349.

[4] a) P. Knochel , MCP Yeh , SC Berk , J. Talbert , J. Org. Chem 1988 , 53, 2390; b) P. Knochel , N. Millot , AL Rodriguez , CE Tucker , Org. React . 2001 , 58, 417.

[5] P. Torsten , P. Thomas , G. Guido , S. Wolfgram . Eur. Pat. Appl . ( 2002 ).

[6] The direct insertion of magnesium in alkenyl halides is not stereoselective. For example, the reaction of (Z) -1-bromooctane with magnesium in THF produces a 15:85 E: Z mixture of 1-octenylmagnesium bromide. The same behavior is observed for the insertion of zinc dust in alkenyl iodides. In both cases, a radical mechanism is the one that operates.

TN Majid and P. Knochel , Tetrahedron. Lett ., 1990 , 31, 4413.

[7] I. Sapountzis , W. Dohle , P. Knochel , Chem. Commun . 2001 , 2068.

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References cited in the description

This list of references cited by the Applicant is only for the convenience of the reader. This one does not form part of the European patent document. Although there has been a lot Be careful when compiling references, you cannot exclude errors or omissions, so the EPO declines any responsibility to this respect.

Non-patent related bibliography cited in the description

The chemistry of the metal-carbon bond. John Wiley & Sons , 1987 , vol. 4 [0025]

A. BOUDIER ; THE BROMM ; M. LOTZ ; P. KNOCHEL . Angew Chem ., 2000 , vol. 112, 4584 [0066]

Angew. Chem. Int . Ed. 2000 , vol. 39, 4414 [0066]

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P. KNOCHEL ; W. DOHLE ; N. GOMMERMANN ; FF KNEISEL ; F. KOPP ; T. KOM ; I. SAPOUNTZIS ; VA VU Angew Chem ., 2003 , vol. 115, 4438 [0066]

Angew. Chem. Int. Ed ., 2003 , vol. 42, 4302 [0066]

L. BOYMOND ; M. ROTTLÄNDER ; G. CAHIEZ ; P. KNOCHEL . Angew Chem ., 1998 , vol. 110, 1801 [0066]

Angew. Chem. Int . Ed., 1998 , vol. 37, 1701 [0066]

M. ABARBRI ; F. DEHMEL ; P. KNOCHEL . Tetrahedron Lett ., 1999 , vol. 40, 7449 [0066]

K. KITAGAWA ; TO INOUE ; H. HINOKUBO ; K. OSHIMA . Angew Chem ., 2000 , vol. 112, 2594 [0066]

Angew. Chem. Int . Ed. 2000 , vol. 39, 2481 [0066]

INOUE ; K. KITAGAWA ; H. SHINOKUBO ; K. OSHIMA . J. Org. Chem ., 2001 , vol. 66, 4333 [0066]

A. INOUE ; K. KITAGAWA ; H. SHINOKUBO ; K. OSHIMA . Tetrahedron , 2000 , vol. 56, 9601 [0066]

F. TRÉCOURT ; G. BRETON ; V. BONNET ; F. MONGIN ; F. MARSAIS ; G. QUEGUINER . Tetrahedron Lett ., 1999 , vol. 40, 4339 [0066]

F. TRÉCOURT33; G. BRETON ; V. BONNET33; F. MONGIN ; F. MARSAIS ; G. QUÉGUINER . Tetrahedron , 2000 , vol. 56, 1349 [0066]

P. KNOCHEL ; MCP YEH ; SC BERK ; J. TALBERT . J. Org. Chem ., 1988 , vol. 53, 2390 [0066]

P. KNOCHEL ; N. MILLOT ; TO RODRIGUEZ ; CE TUCKER . Org. React ., 2001 , vol. 58, 417 [0066]

P. TORSTEN ; P. THOMAS ; G. GUIDO ; S. WOLFGRAM . Eur. Pat. Appl ., 2002 [0066]

TN MAJID ; P. KNOCHEL . Tetrahedron Lett ., 1990 , vol. 31, 4413 [0066]

I. SAPOUNTZIS ; W. DOHLE ; P. KNOCHEL . Chem. Commun ., 2001 , 2068 [0066]

Claims (16)

1. Reagent with the general formula: R 1 (MgX) n • LiY in where

quad

n is 1 or 2;

quad

R 1 is a C 4 -C 24 aryl substituted or unsubstituted or a heteroaryl C 3 -C 24, which contains one or more heteroatoms such as B, O, N, S, Se, P, F, Cl, Br, I, or Si; an alkyl C 1 -C 20, alkenyl C 2 -C 20 or an alkynyl C 2 -C 20 linear or branched, substituted or unsubstituted; or a cycloalkyl C 3 -C 20 substituted or not replaced;

quad

X and Y are independently or both Cl, Br or I, preferably Cl; HalO_ {n} (where n = 3, 4); Cl; Carboxylate of formula RCO2; alkoxide or phenoxide of formula RO; dialkoxide of formula LiO-R-O; disilazide of formula (R 3 Si) 2 N; thiolate of formula SR; RP (O) O2; or SCOR; where R is defined as R1 higher;

quad

linear C 1 -C 20 alkyl or branched, substituted or unsubstituted or C 3 -C 20 cycloalkyl amines of formula RNH; dialkyl / arylamine of formula R 2 N (where R is defined as more above or R2 N represents a heterocyclic alkylamine); phosphine of formula PR2 (where R is defined as above or PR2 represents a heterocyclic phosphine); O_ {n} SR (where n = 2 or 3 and R is defined as above); or NO_ {n} (where n = 2 or 3); or X = R1 as defined above.

2. Reagent according to claim 1, wherein The reagent is (R 1) 2 Mg-LiY. 3. Reagent according to claim 1, wherein the reagent comprises R1 (MgX) n and LiY in a molar ratio 0.05-6.0. 4. Reagent according to the claims 1-3, where Y is Cl, tert-butylate or sec-butylate. 5. Reagent according to any of the claims 1 or 3, 4, which is i-PrMgCl-LiCl or sec-BuMgCl \ cdotLiCl, in a molar relationship between i-PrMgCl or sec-BuMgCl and LiCl of 0.05 to 6.0. 6. Procedure for the preparation of organomagnesic compounds, comprising the following Steps: a) provide a compound that has the General Formula: R2 A; in where,

quad

R 2 is defined as R 1; or a metallocene substituted or unsubstituted as ferrocene;

quad

A is H, Cl, Br, I, preferably Br, or a group of General Formula:

S (O) n -R 3

quad

where,

quad

n = 0, 1 or 2

quad

or to a group of general formula:

P (O) R 3 {2}

quad

where,

quad

R3 is independently defined as R1;

quad

or P (O) R 3 2 represents a heterocyclic phosphinoxide;

b) provide a reagent according to one or more claims from 1 to 5; c) make the reaction of the compounds provided in steps a) and b) under the appropriate conditions; and therefore, obtaining the organomagnesic compound.

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7. Method according to claim 6, in wherein the reagent according to any one of claims 1 to 5, it is provided by reaction of R 1 X, Mg and LiY or by the reaction of R 1 Li and MgXY. 8. Procedures according to any of the claims 6 and 7, wherein the compound provided in the step b) is used in a molar amount of 0.4-0.6 per mole of the compound provided in step a). 9. Procedure according to any of the claims 6 to 8, wherein the compound provided in the step b) is used as a solution in a suitable solvent. 10. Method according to claim 9, in where the solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, dibutyl ether, diethyl ether, tert-butylmethyl ether, dimethoxyethane, dioxanes, preferably 1,4-dioxane, triethylamine, pyridine, ethyldiisopropylamine, dichloromethane, 1,2-dichloromethane, dimethylsulfoxide, dimethylsulfide, benzene, toluenes, xylene, pentane, hexane, heptane, or combinations thereof. 11. Method according to claim 9 or 10, wherein the solution additionally contains one or more additives selected from polyethers or polyamines, in particular crown ethers, dioxanes, oligo- or polyethylene glycol ethers, derivatives urea, amides of formula RCONR2 (where R is defined as in the claim 1, the radicals may be the same or different), more preferably 1,4-dioxane or 15-crown-5, or combinations of same. 12. Method according to claims 9 a 11, wherein the solution is 0.05 to 3.0 M, preferably 1.0-2.5 M. 13. Procedure for preparing compounds organic functionalized or non-functionalized, which include the Steps a) -c) of one or more claims of 6 to 12, and d) reaction of the organomagnesic compound obtained with a organic or inorganic electrophile E + or E. 14. Procedure according to any of the claims 6 to 13, which is carried out at a temperature in the range between -78ºC to 80ºC, preferably at room temperature. 15. Reagent use according to any of claims 1 to 5 in the preparation of compounds Organomagnesics and their reaction with electrophiles. 16. Organomagnesic compound, which is obtainable by the method according to any of the claims from 6 to 14.